Research focus

​Genetics has shown that mutations in functionally related genes (Presenilins (PSEN) and Amyloid Precursor Protein (APP)) cause Alzheimer’s disease (AD) with early onset. PSEN is the catalytic subunit of the γ-secretase intramembrane proteases, which sequentially cleave APP to generate Aβ peptides. Alzheimer’s disease-causing mutations consistently lead to production of longer amyloidogenic Aβ peptides and this points at the shift in Aβ length as fundamental to the disease pathogenic mechanism. The mutant-induced changes in Aβ profiles as well as the Aβ-mediated neurotoxicity mechanism are poorly defined.

We are interested in generating a quantitative understanding of the molecular mechanisms underlying Alzheimer’s disease pathogenicity. Our research is based on the premise that getting a better mechanistic understanding of the function of the molecules involved in familial Alzheimer’s disease (FAD) will offer critical insights into the molecular basis of the disease and open new research avenues leading to innovative and safe strategies to tackle the disease in the clinic.

Our interest extends to the study of the relationships between function and structure that govern γ-secretase proteolysis. Our previous studies depict γ-secretase as a dynamic ensemble of distinct conformational states, which equilibrium is “remodelled” by protease inhibition or the presence of a familial AD-linked PSEN mutations (Elad et al., 2015). We use Nanobodies as conformational probes to investigate the conformational landscape of these complex proteases.​​​​

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21/03/2019 - VIB is very grateful to the Alzheimer Research Foundation for funding the researchers received, which helps them in their quest for cures. The ​Foundation has been fighting Alzheimer's disease for years and is working on a future without dementia.